EP0486900B1 - Procédé pour la préparation d'indoles - Google Patents

Procédé pour la préparation d'indoles Download PDF

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Publication number
EP0486900B1
EP0486900B1 EP91119053A EP91119053A EP0486900B1 EP 0486900 B1 EP0486900 B1 EP 0486900B1 EP 91119053 A EP91119053 A EP 91119053A EP 91119053 A EP91119053 A EP 91119053A EP 0486900 B1 EP0486900 B1 EP 0486900B1
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EP
European Patent Office
Prior art keywords
hydrogen
phenylhydrazine
process according
sodium
branched
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EP91119053A
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German (de)
English (en)
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EP0486900A3 (en
EP0486900A2 (fr
Inventor
Heinz Ulrich Dr. Blank
Friedrich-Wilhelm Dr. Ullrich
Karlheinrich Dr. Meisel
Willi Dr. Streicher
Nikolaus Dr. Schulz
Dieter Dipl.-Ing. Irmscher
Günther Dr. Klag
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Bayer AG
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Bayer AG
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system

Definitions

  • the present invention relates to a process for the preparation of indoles by cyclization of phenylhydrazones, which are formed from phenylhydrazine and ketones, in the presence of less than 5 equivalents of sodium hydrogen sulfate.
  • Indoles are important intermediates in the dye industry. It is known to cyclize phenylhydrazones in organic media using Lewis or protonic acids, for example in ethanol in the presence of zinc chloride (Chem. Zeitg. 22 (1898), 38), in glacial acetic acid as the reaction medium (J. Org. Chem. 42 (1977), 2474), in chloroform in the presence of polyphosphoric acid ester (Chem. And Ind. 1965 , 473). Furthermore, such a reaction is described in polyphosphoric acid without further solvent addition (J. Am. Chem. Soc. 74 (1952), 3948).
  • indole synthesis in aqueous reaction medium can also be carried out with sodium hydrogen sulfate in short reaction times with good yields, using less than 5 equivalents of sodium hydrogen sulfate, based on the phenylhydrazine.
  • This is all the more surprising since it is known from DE-OS 19 06 832 that when using substituted aliphatic or aromatic acids, the pK value of which is close to 1.3, large amounts of acid and long reaction times are required in order to obtain satisfactory yields achieve.
  • Suitable phenylhydrazines for the process according to the invention are: Phenylhydrazine, 4-methylphenylhydrazine, 4-dodecylphenylhydrazine, 2,5-dimethylphenylhydrazine, 3,4-dimethylphenylhydrazine, 4-methoxyphenylhydrazine, 4-hydroxyphenylhydrazine, 4-chlorophenylhydrazine, 5-chloro-2-methylphenylhydrazine, 2,4-dichlorophenylhydrazine.
  • Suitable ketones for the process according to the invention are: 2-butanone, 3-methyl-2-butanone, 3-pentanone, 4-methyl-2-pentanone, cyclohexanone, 2-methylcyclohexanone, 2-dodecanone.
  • Sodium hydrogen sulfate is used in an amount of less than 5 equivalents per 1 mol of the phenylhydrazine used, preferably in an amount of 1-4.9 equivalents, particularly preferably 1.5-4.5 equivalents, very particularly preferably 2-4 equivalents.
  • the process according to the invention is carried out at a temperature of 50-150 ° C., preferably 80-110 ° C.
  • both the phenylhydrazine and the ketone can be initially introduced together with sodium hydrogen sulfate in an aqueous medium, brought to the reaction temperature and then the reaction component which is still missing is added. It is often advantageous to present the phenylhydrazine. It is also possible to add the phenylhydrazine and the ketone simultaneously to the aqueous medium at the reaction temperature with sodium bisulfate; it may also be advantageous here to provide some phenylhydrazine and then to add both components simultaneously. The simultaneous addition is suitable also for a continuous way of working. In all cases, the formation of the phenylhydrazone and its cyclization to the indole take place in succession with NH 3 elimination.
  • the reaction mixture is neutralized.
  • the indole is obtained as an organic phase; if necessary, the indole can be further purified in a manner familiar to the person skilled in the art.
  • the saline aqueous phase which is obtained during the neutralization, is disposed of in a known manner. This salt load requiring disposal is smaller in the process according to the invention than in conventional indole syntheses.
  • a phenylhydrazine is used which is prepared from the associated sodium phenylhydrazodisulfonate and / or the associated sodium phenylhydrazo- ⁇ -sulfonate by adding sulfuric acid. This preparation generally takes place in the presence of residual sodium sulfite and / or sodium hydrogen sulfite, which had been used to form the hydrazosulfonates.
  • the amount of sulfuric acid required is set for the use of such a phenylhydrazine such that the remaining sodium sulfite, sodium bisulfite and the sulfate split off from the hydrazosulfonate are used less than 5 equivalents of sodium hydrogen sulfate per mole of phenylhydrazine.
  • the ketone is then added to such a phenylhydrazine, which contains the stated amount of sodium hydrogen sulfate, and the process according to the invention is carried out as described in more detail above.
  • aqueous benzene diazonium chloride solution prepared by conventional methods from 2 moles of aniline, 4.2 moles of hydrochloric acid and 2.02 moles of sodium nitrite was reacted according to known methods with 5.2 moles of a mixture of sodium sulfite and sodium bisulfite to give a phenylhydrazodisulfonate solution.
  • 80 ° C were too 150 ml of 48% sulfuric acid (1 mol) were added dropwise to this solution. The mixture was stirred at 80 ° C. for 2 h, then 225 ml (2.1 mol) of methyl isopropyl ketone were metered in over 30 min.
  • aniline was diazotized with hydrochloric acid and sodium nitrite in a molar ratio of 1: 2.3: 1.07.
  • This diazonium salt solution was also continuously reacted with 2.55 mol of sodium sulfite / bisulfite mixture per mol of aniline to give a phenylhydrazodisulfonate solution.
  • a portion of this mixture, corresponding to 1.91 mol of aniline, was added dropwise at 80 ° C. to 200 ml of a 48% sulfuric acid (1.35 mol). After a reaction time of 2 h at 80 ° C., 225 ml (2.1 mol) of methyl isopropyl ketone were metered in in 30 min. After a reaction time of 3 h at 95 to 100 ° C., the mixture was cooled. The mixture was neutralized, the organic phase was separated off and distilled.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)

Claims (8)

  1. Procédé de préparation des 1-H- et 3-H-indoles de formules respectives
    Figure imgb0019
     par réaction d'une phénylhydrazine non substituée dans au moins une position ortho et répondant à la formule
    Figure imgb0020
     avec une cétone de formule
    Figure imgb0021
     en milieu aqueux, en présence d'un composé acide, les symboles des formules ci-dessus ayant les significations suivantes :
    R1 représente l'hydrogène,
    R2 représente un groupe méthyle,
    R3 représente l'hydrogène ou un groupe méthyle,
    R1 pouvant en outre représenter un groupe méthyle lorsque R3 représente l'hydrogène,
    R1 et R2 peuvent également former ensemble un groupe triméthylène et
    R2 peut en outre représenter un groupe isopropyle, n-butyle ou n-nonyle lorsque
    R1 et R3 représentent l'hydrogène,
    R6 et R7 représentent chacun, indépendamment l'un de l'autre, l'hydrogène, un groupe alkyle à chaîne droite ou ramifiée en C1-C12, un groupe alcoxy à chaîne droite ou ramifiée en C1-C4, un groupe phényle, phénoxy, un halogène, un groupe hydroxy, nitro, cyano ou N(R8,R9),
    R6 pouvant en outre représenter CON(R8R9), COR8 ou COOR8 et
    R8 et R9 représentent chacun, indépendamment l'un de l'autre, l'hydrogène ou un groupe alkyle à chaîne droite ou ramifiée en C1-C4,
    caractérisé en ce que l'on met en oeuvre du bisulfate de sodium en quantité inférieure à cinq équivalents pour une mole de phénylhydrazine.
  2. Procédé selon la revendication 1, caractérisé en ce que l'on met en oeuvre une phénylhydrazine ayant au moins une position ortho non substituée et répondant à la formule
    Figure imgb0022
     dans laquelle
    R16 et R17 représentent chacun, indépendamment l'un de l'autre, l'hydrogène, un groupe alkyle à chaîne droite ou ramifiée en C1-C12, un groupe alcoxy à chaîne droite ou ramifiée en C1-C4, un groupe phényle, phénoxy, un halogène, un groupe hydroxy, cyano ou N(R18,R19),
    R18 et R19 représentant chacun, indépendamment l'un de l'autre, l'hydrogène, un groupe méthyle ou éthyle,
    de préférence une phénylhydrazine ayant au moins une position ortho non substituée et répondant à la formule
    Figure imgb0023
     dans laquelle
    R26 et R27 représentent chacun, indépendamment l'un de l'autre, l'hydrogène, un groupe méthyle, éthyle, méthoxy, éthoxy ou un halogène, R26 pouvant en outre représenter un groupe hydroxy ou N(R18,R19).
  3. Procédé selon la revendication 1, caractérisé en ce que l'on met en oeuvre de 1 à 4,9 équivalents, de préférence de 1,5 à 4,5 équivalents et tout spécialement de 2 à 4 équivalents de bisulfate de sodium par mole de phénylhydrazine.
  4. Procédé selon la revendication 1, caractérisé en ce que l'on opère à des températures de 50 à 150°C, de préférence de 80 à 110°C.
  5. Procédé selon la revendication 1, caractérisé en ce que l'on met en oeuvre une phénylhydrazine qui a été préparée à partir du phénylhydrazodisulfonate alcalin correspondant et/ou du phénylhydrazo-β-sulfonate alcalin correspondant en présence du sulfite de sodium et/ou du bisulfite de sodium résiduels par addition d'acide sulfurique.
  6. Procédé selon la revendication 5, caractérisé en ce que l'on règle la quantité d'acide sulfurique en sorte que le sulfate libéré à partir du sulfite et du bisulfite de sodium résiduel et de l'hydrazosulfonate, représente moins de 5 équivalents de bisulfate de sodium par mole d'hydrazine.
  7. Procédé selon la revendication 5, caractérisé en ce que la scission du groupe sulfonate à partir du phénylhydrazodisulfonate de sodium et/ou du phénylhydrazo-β-sulfonate de sodium est réalisée en présence de la cétone et en ce que la synthèse de l'indole est réalisée dans le même milieu sans isolement préalable de la phénylhydrazine.
  8. Procédé selon la revendication 7, caractérisé en ce que, pour la préparation de l'indole, on part d'une aniline non substituée dans au moins une position ortho et répondant à la formule
    Figure imgb0024
     dans laquelle R6 et R7 représentent chacun, indépendamment l'un de l'autre, l'hydrogène, un groupe alkyle à chaîne droite ou ramifiée en C1-C12, un groupe alcoxy à chaîne droite ou ramifiée en C1-C4, un groupe phényle, phénoxy, un halogène, un groupe hydroxy, nitro, cyano ou N(R8,R9),
    R6 pouvant en outre représenter CON(R8,R9), COR8 ou COOR8, et on procède aux opérations de diazotation, de réduction du sel de diazonium à l'aide d'un sulfite, de scission du groupe sulfonate et finalement de réaction avec la cétone sans isoler les produits intermédiaires.
EP91119053A 1990-11-21 1991-11-08 Procédé pour la préparation d'indoles Expired - Lifetime EP0486900B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4037004A DE4037004A1 (de) 1990-11-21 1990-11-21 Verfahren zur herstellung von indolen
DE4037004 1990-11-21

Publications (3)

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EP0486900A2 EP0486900A2 (fr) 1992-05-27
EP0486900A3 EP0486900A3 (en) 1992-08-19
EP0486900B1 true EP0486900B1 (fr) 1996-09-04

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US (1) US5179211A (fr)
EP (1) EP0486900B1 (fr)
JP (1) JPH04266871A (fr)
DE (2) DE4037004A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6133453A (en) * 1998-05-15 2000-10-17 Pharm-Eco Laboratories, Inc. Method for making substituted indoles
MX2011006564A (es) 2008-12-19 2011-09-26 Amgen Inc Procedimiento mejorado para la preparacion de 1-acetil-6-amino-3,3-dimetil-2,3-dihidroindol.

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE574840C (de) * 1931-11-01 1933-04-20 I G Farbenindustrie Akt Ges Verfahren zur Darstellung von Indolen
US3639420A (en) * 1968-02-21 1972-02-01 Toms River Chemical Corp Process for the preparation of 2 3 3-trimethyl indolenines
IT1015908B (it) * 1974-04-05 1977-05-20 Snam Progetti Procedimento per la sintesi di indolenine alchil sostituite
FR2275461A1 (fr) * 1974-06-18 1976-01-16 Labaz Nouveaux stabilisants des polymeres et copolymeres du chlorure de vinyle

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Publication number Publication date
JPH04266871A (ja) 1992-09-22
EP0486900A3 (en) 1992-08-19
DE4037004A1 (de) 1992-05-27
EP0486900A2 (fr) 1992-05-27
US5179211A (en) 1993-01-12
DE59108138D1 (de) 1996-10-10

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